This proposal examines the role of lipid mediators (platelet activating factor (PAF) and eicosanoids including cyclooxygenase, lipoxygenase and monooxygenase products of arachidonic acid) in endotoxin-induced pulmonary dysfunction. Special attention is given to the alterations in lung mechanics and airway responsiveness caused by endotoxin. The Specific Aims are: 1. To determine the direct and secondary effects of purified lipid mediators on lung function in vivo and on cells and lung tissue in vitro. 2. To determine the quantity, timing and pattern of release of lipid mediators following endotoxin exposure in vivo and in vitro. 3. To determine the effects of receptor antagonists and inhibitors of PAF and eicosanoid metabolism on endotoxin-induced lipid mediator release and pulmonary dysfunction in chronically instrumented awake sheep. State-of-the-art analytic methods and a natural skepticism about the specificity of pharmacologic probes are used to carefully define the roles of individual mediators and interactions, if any, among lipid mediators in endotoxin-induced pulmonary dysfunction. It is the long-term objective of this proposal to gain understanding that will assist in the development of interventions relevant to the prevention or treatment of the adult respiratory distress syndrome (ARDS) and asthma in man.